Use of Thiol Compounds to Treat Neurological Disease

ABSTRACT

The present disclosure relates, in general, to use of small diffusible thiols in the treatment of neurodegenerative diseases associated with glutamate excitotoxicity, protein aggregation and oxidative stress in the central nervous system, particularly in the brain.

FIELD OF THE DISCLOSURE

The present disclosure relates, in general, to use of small diffusiblethiols in the treatment of neurodegenerative diseases associated withglutamate excitotoxicity, protein aggregation and oxidative stress inthe central nervous system, particularly in the brain.

BACKGROUND

Endogenous thiols, primarily cysteine and its derivatives, act aselectron sources and transfer mediators, ensuring the homeostaticmaintenance of organellar redox states, especially in the mitochondria(25-34). As strong coordination ligands, they allow proteins to accessmetal ion chemistry, which are fundamental to the generation of energyand electron-rich cellular currencies but may be dangerous when notproperly controlled (35-41). It has been shown that upon ingestion,cysteamine or cystamine can increase levels of cysteine in blood bycleaving cystine (9-11). This effect, in turn, increases brain andintracellular sulfur amino acid levels by increasing flux throughunderutilized pathways, overcoming the lack of cystine transport acrossthe BBB, and easing reliance on cystine-glutamate exchange within theparenchyma (12-24).

Neurodegeneration is characterized by oxidative depletion of nativethiols. Another feature of neurodegeneration is intracellular proteinaggregation (42-59). Organelle-specific protein aggregates inhibittranscription, RNA processing, axonal transport and mitochondrialfunction (42,47,55,57,60). Pathogenic aggregation is gated by cysteineoxidation in least three proteins, tau, SOD1 and TDP-43(44-46,48,56,61,62). Aggregates of these proteins are found inamyotrophic lateral sclerosis (ALS), chronic traumatic encephalopathy(CTE) and Alzheimer's disease (39,50,52,63,64). Thiols have been shownto reduce and, in the early stages, reverse, some protein aggregateformation (43-45,56,61).

SUMMARY OF THE DISCLOSURE

Low-molecular weight aminothiols, or captons as used herein, areselected for optimal reactivity, metabolic stability, pharmacokineticpersistence and oral bioavailability for use in treatingneurodegenerative diseases. Captons are unique in their display ofGABAergic or taurinergic activity after thiol oxidation upon crossing ofthe Blood Brain Barrier (BBB).

Provided herein is a method of treating a neurological disease ordisorder comprising administering a small thiol compound (<500 daltons,log P >0.8, TPSA <90) that can be oxidized by reactive-oxygen speciesafter crossing the blood-brain barrier to a sulfinic or sulfonic acidand wherein the oxidized compound possesses GABAergic, calcium channelinhibiting, glutamatergic or other neurologic activity.

Also provided is a method of treating an excitotoxicity disordercomprising administering a small thiol compound having a molecularweight <500 daltons, a log P >0.8, and a TPSA <90 that can be oxidizedby reactive-oxygen species after crossing the blood-brain barrier to asulfinic or sulfonic acid and where the oxidized compound possessesGABAergic, calcium channel inhibiting, glutamatergic or other neurologicactivity.

Further contemplated is a method of treating a neurological disease ordisorder characterized by aggregation of TDP-43 comprising administeringa small thiol compound having a molecular weight <500 daltons, a logP >0.8, and a TPSA <90 that can be oxidized by reactive-oxygen speciesafter crossing the blood-brain barrier to a sulfinic or sulfonic acidand where the oxidized compound possesses GABAergic, calcium channelinhibiting, glutamatergic or other neurologic activity.

The disclosure also provides a method of treating a neurological diseaseor disorder characterized by aggregation of superoxide dismutase 1(SOD1) protein comprising administering a small thiol compound having amolecular weight <500 daltons, a log P >0.8, and a TPSA <90 that can beoxidized by reactive-oxygen species after crossing the blood-brainbarrier to a sulfinic or sulfonic acid and where the oxidized compoundpossesses GABAergic, calcium channel inhibiting, glutamatergic or otherneurologic activity.

In various embodiments, the disease is further characterized byaggregation of tau protein.

In various embodiments, the disease or disorder is amyotrophic lateralsclerosis (ALS), frontotemporal lobar degeneration, traumatic braininjury, chronic traumatic encephalopathy (CTE), Alzheimer's disease,ischemia or epilepsy. In various embodiments, the disease is familial orsporadic ALS.

The disclosure further contemplates a method of preventing orameliorating brain injury caused by trauma comprising administering to asubject in need thereof a small thiol compound having a molecular weight<500 daltons, a log P >0.8, and a TPSA <90 that can be oxidized byreactive-oxygen species after crossing the blood-brain barrier to asulfinic or sulfonic acid and where the oxidized compound possessesGABAergic, calcium channel inhibiting, glutamatergic or other neurologicactivity. prior to the subject undertaking activity in which the brainmay be injured.

In various embodiments, the disclosure provides a method for protectingneurons from trauma and injury comprising administering to a subject inneed thereof a small thiol compound.

In various embodiments, the compound reduces protein aggregation,neuronal overexcitation or oxidative stress characteristic ofneurodegenerative disorders.

Contemplated herein is a method for treating or ameliorating glutamatetoxicity in a subject comprising administering an effective amount of asmall thiol compound having a molecular weight <500 daltons, a logP >0.8, and a TPSA <90 that can be oxidized by reactive-oxygen speciesafter crossing the blood-brain barrier to a sulfinic or sulfonic acidand where the oxidized compound possesses GABAergic, calcium channelinhibiting, glutamatergic or other neurologic activity.

In various embodiments, the administration reduces neuronal glutamatetoxicity.

It is contemplated that the small diffusible thiol compound useful inany one of the methods is a capton as described herein. Exemplarycaptons are set out in FIGS. 1 and 2, in Formulas I, II and III, inTable A, and described further in the detailed description.

Further provided is a method for slowing the degeneration of neurons ina subject comprising administering an effective amount of a compound ofFormula I, II or III, Table A, or a small thiol compound having amolecular weight <500 daltons, a log P >0.8, and a TPSA <90 that can beoxidized by reactive-oxygen species after crossing the blood-brainbarrier to a sulfinic or sulfonic acid and where the oxidized compoundpossesses GABAergic, calcium channel inhibiting, glutamatergic or otherneurologic activity.

Also contemplated is a method for treating or ameliorating glutamatetoxicity in a subject comprising administering an effective amount of acompound of Formula I, II or III, Table A, or a small thiol compoundhaving a molecular weight <500 daltons, a log P >0.8, and a TPSA <90that can be oxidized by reactive-oxygen species after crossing theblood-brain barrier to a sulfinic or sulfonic acid and where theoxidized compound possesses GABAergic, calcium channel inhibiting,glutamatergic or other neurologic activity.

In various embodiments, disclosed are methods of using compounds ofFormula (I):

wherein:

R¹ and R² are independently selected from the group consisting of H andC₁₋₆alkyl; or

R¹ and R², taken together with the carbon atom to which they areattached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

R³ and R⁴ are independently selected from the group consisting of H andC₁₋₆alkyl; or

R³ and R⁴, taken together with the carbon atom to which they areattached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

G is selected from the group consisting of —NR⁵R⁶ and —CR⁷R⁸NR⁵R⁶;

R⁵ and R⁶ are independently selected from the group consisting of H andC₁₋₆alkyl; or

R⁵ and R⁶, taken together with the nitrogen atom to which they areattached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring;

R⁷ and R⁸ are independently selected from the group consisting of H andC₁₋₆alkyl; or

R⁷ and R⁸, taken together with the carbon atom to which they areattached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

R² and R⁶, taken together with the atoms to which they are attached,optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclicring;

R⁴ and R⁶, taken together with the atoms to which they are attached,optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclicring;

R⁴ and R⁸, taken together with the atoms to which they are attached,optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

R² and R⁸, taken together with the atoms to which they are attached,optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

R² and R⁴, taken together with the atoms to which they are attached,optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

wherein a C₁₋₅ alkyl moiety, wherever it occurs, can optionally comprisea double bond; and

wherein a C₁₋₅ alkyl, 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic orheterocyclic moiety, wherever it occurs, can optionally be substitutedwith from one to three substituents which are not further substitutedand which are independently selected from the group consisting of —CN,thio, halo, hydroxy, C₆₋₁₀ aryl, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₆cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3heteroatoms selected from O, N, and S, CO₂H, CO₂C₁₋₆alkyl,C(O)C₁₋₆alkyl, CO₂NH₂, CO₂NHC₁₋₆alkyl, and —CO₂N(C₁₋₆alkyl)₂.

In various embodiments, disclosed are methods of using a compound ofFormula II:

HS-L-NR⁹R¹⁰  (II),

wherein:

L is a hydrocarbon linking group;

R⁹ and R¹⁰ are independently selected from the group consisting of H,C₁₋₅alkyl, and CO(C₁₋₅alkyl); or

R⁹ and R¹⁰, taken together with the nitrogen atom to which they areattached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring;

wherein a C₁₋₆ alkyl moiety, wherever it occurs, can optionally comprisea double bond; and

wherein a C₁₋₆ alkyl, 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic orheterocyclic moiety, wherever it occurs, can optionally be substitutedwith from one to three substituents which are not further substitutedand which are independently selected from the group consisting of —CN,thio, halo, hydroxy, C₆₋₁₀ aryl, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₆cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3heteroatoms selected from O, N, and S, CO₂H, CO₂C₁₋₆alkyl,C(O)C₁₋₆alkyl, CO₂NH₂, CO₂NHC₁₋₆alkyl, and —CO₂N(C₁₋₆alkyl)₂.

In various embodiments, disclosed are methods of using a compound ofFormula (III):

wherein:

A is a 3 to 8 membered heterocyclic ring containing one N atom;

n is 0, 1, 2, or 3; and

wherein a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic moiety,wherever it occurs, can optionally be substituted with from one to threesubstituents which are not further substituted and which areindependently selected from the group consisting of —CN, thio, halo,hydroxy, C₆₋₁₀ aryl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, 5- or6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O,N, and S, CO₂H, CO₂C₁₋₆alkyl, C(O)C₁₋₆alkyl, CO₂NH₂, CO₂NHC₁₋₆alkyl, and—CO₂N(C₁₋₆alkyl)₂.

In various embodiments, disclosed are methods of using compounds ofFormula I, II or III that have SeH instead of SH.

In various embodiments, the administration improves one or more symptomsof a neurodegenerative disorder or excitotoxicity disorder. In variousembodiments, the one or more symptom is diminished motor function,mobility, cognitive ability, or other symptoms of an excitotoxicitydisorder. In one embodiment, one or more symptoms include diminishedmotor function, mobility, cognitive ability, or other symptoms of anexcitotoxicity disorder.

In various embodiments, the small thiol compound exhibitsneuroprotective effects in a neuronal tissue-culture model ofexcitotoxicity, oxidative stress, glutamate overstimulation, elevatedintracellular calcium, GABA receptor function, mitochondrial stress orthe consequences of these phenomena.

In various embodiments, the small thiol compound or its oxidizedequivalent improves cell-viability, reduces calcium transport, relievesmitochondrial stress, enhances mitophagy, modulates GABA activity,modulates glutamate activity or inhibits voltage-gated calcium channelactivity in a subject.

In various embodiments, the thiol compound; i) reduces levels of ROS inthe CNS; ii) increases intracellular cysteine and the sum of allintracellular low-molecular weight thiols; iii) reduces weakmetal-protein interactions through binding of unchaperoned metal-ions;and/or iv) reduces intracellular protein aggregation that is dependenton oxidation of cysteine.

Also contemplated herein is a composition comprising a capton asdescribed herein, (e.g., in FIG. 1 or 2, Formulas I, II or II, Table A,and as described in the Detailed Description), the compositionoptionally comprising a pharmaceutically acceptable carrier, excipientor diluent. A composition comprising a capton and optionally apharmaceutically acceptable carrier is contemplated for use in any oneof the methods herein.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts representative capton compounds.

FIG. 2 shows additional capton compounds, including the effect of thiolsubstitution (of the original oxoanion molecule) on the blood brainbarrier (BBB) penetration aptitude (log P and total polar surface area).tPSA >90 signifies an inability to cross the BBB. Typically, the higherthe tPSA, the lower brain penetration. Oxidization of thiol-substitutedcompounds increases tPSA.

FIG. 3 shows the oxidation of 2-aminocyclohexanethiol by peroxide alone,or in the presence of Fe(II) or Cu(I).

FIG. 4 shows the EC₅₀ determination for oxidation of2-aminocyclohexanethiol by peroxide in the presence of catalytic Cu(I).

FIG. 5 shows the in vitro oxidation of 2-aminocyclohexanethiol(capton-004) and piperidine-3-thiol (capton-003) by hydrogen peroxide inthe absence of metals.

FIG. 6 shows the concentrations of ocapton-003 and ocapton-004 in a ratbrain model following treatment with kainate.

FIG. 7 shows the ratio of ocapton to capton for captons 003 and 004 in arat brain model with and without treatment with kainate.

FIG. 8 shows pharmacokinetic profiles for capton-004 in a nonkainate-treated rat model.

FIG. 9 shows pharmacokinetic profiles for capton-004 in akainate-treated rat model.

DETAILED DESCRIPTION

It is contemplated herein that intracellular capton thiols may mitigateoxidation-dependent protein aggregation through reductive mechanismsacting on disulfides and other oxidized sulfur species. Proteinaggregation is a fundamental feature of neurodegeneration.Protein-specific assays have been developed to measure aggregation inneurons as a result of oxidative stress, a key driver of aggregation forat least three pathogenic proteins, SOD1, tau and TDP-43. Captons mayreduce or reverse aggregation directly or indirectly. Stabilized by aproximate, positively-charged amine, the capton thiol is more acidicthan endogenous, low-molecular weight thiols, resulting in elevatedthiolate levels under physiological conditions. This feature may haveconsequences on the kinetics of intracellular disulfide exchange,increasing reduction rates. Paradoxically, a free capton thiolate isthermodynamically-favored. This combination of kinetic and thermodynamiceffects will render the capton an effective catalyst of disulfideexchange, allowing disulfide networks to efficiently access lower energyconfigurations.

Oxidation of capton thiols by ROS is catalyzed by metal ions, includingcopper, iron and zinc (65-68). Loss of metal homeostasis is a hallmarkof ALS (35,36), Alzheimer's and Parkinson's diseases (38,69,70). Thiolsbind strongly to copper, iron and zinc. Aminothiols are good metalbinders, a result of chelation effects when both sulfur and nitrogenheteroatoms participate in metal complex formation. One mechanism bywhich the present captons may work is through interaction of captonswith free metal ions. Captons may act directly with free metal ions inthe extracellular space of the brain through ligand-metal coordinationor indirectly by catalyzing the oxidation of thiols.

Definitions

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “a derivative”includes a plurality of such derivatives and reference to “a patient”includes reference to one or more patients and so forth.

Also, the use of “or” means “and/or” unless stated otherwise. Similarly,“comprise,” “comprises,” “comprising” “include,” “includes,” and“including” are interchangeable and not intended to be limiting.

It is to be further understood that where descriptions of variousembodiments use the term “comprising,” those skilled in the art wouldunderstand that in some specific instances, an embodiment can bealternatively described using language “consisting essentially of” or“consisting of.”

The term “about” or “approximately” means an acceptable error for aparticular value as determined by one of ordinary skill in the art,which depends in part on how the value is measured or determined. Incertain embodiments, the term “about” or “approximately” means within 1,2, 3, or 4 standard deviations. In certain embodiments, the term “about”or “approximately” means within 30%, 25%, 20%, 15%, 10%, 9%, 8%, 7%, 6%,5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range. Wheneverthe term “about” or “approximately” precedes the first numerical valuein a series of two or more numerical values, it is understood that theterm “about” or “approximately” applies to each one of the numericalvalues in that series.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood to one of ordinary skill inthe art to which this disclosure belongs. Although methods and materialssimilar or equivalent to those described herein can be used in thepractice of the disclosed methods and products, the exemplary methods,devices and materials are described herein.

The documents discussed above and throughout the text are providedsolely for their disclosure prior to the filing date of the presentapplication. Nothing herein is to be construed as an admission that theinventors are not entitled to antedate such disclosure by virtue ofprior disclosure. Each document is incorporated by reference in itsentirety with particular attention to the disclosure for which it iscited.

The following references provide one of skill with a general definitionof many of the terms used in this disclosure: Singleton, et al.,DICTIONARY OF MICROBIOLOGY AND MOLECULAR BIOLOGY (2d ed. 1994); THECAMBRIDGE DICTIONARY OF SCIENCE AND TECHNOLOGY (Walker ed., 1988); THEGLOSSARY OF GENETICS, 5TH ED., R. Rieger, et al. (eds.), Springer Verlag(1991); and Hale and Marham, THE HARPER COLLINS DICTIONARY OF BIOLOGY(1991).

As used herein a “capton”, “small thiol”, “small diffusible thiol” or“small diffusible aminothiol” refers generally to a low-molecular weightthiol selected for reactivity, metabolic stability, pharmacokineticpersistence and oral bioavailability. Captons are characterized by theirsimilarity to analogs of the neurotransmitter GABA (γ-aminobutyricacid), the structurally-related amino acid taurine(2-aminoethane-1-sulfonate) or known glutamatergic agents. Captonsdiffer from true GABA and taurine analogs by the presence of a thiol inplace of the required oxoanion functionality, typically a carboxylate(as found in GABA itself) or a sulfonate (as found in taurine itself).Unique among aminothiols with molecular weight <500 daltons, or even 300daltons, captons have taurinergic, GABAergic, calcium channelinhibiting, glutamatergic or other neurologic activity after thioloxidation. Captons may have the following characteristics: small thiolcompound, <500 daltons, log P >0.8, tPSA <90.

As used herein “tPSA” refers to total polar surface area (tPSA), whichis significantly lower in a capton having a thiol substitution thanwithout it (e.g., in a structurally similar GABA analog or target).tPSA >90 signifies an inability to cross the BBB, and, in general, thehigher the tPSA number, the lower brain penetration. Oxidization ofthiol-substituted compounds increases tPSA, and increases in tPSA thatoccur after BBB crossing (e.g., in the oxidized thiol form) areadvantageous by delaying clearance of the compound from the subject.

As used herein, a “therapeutically effective amount” or “effectiveamount” refers to that amount of a small diffusible thiol compositionthat is oxidized to a sulfinic acid or sulfonic acid after crossing theblood brain barrier, sufficient to result in amelioration of symptoms,for example, treatment, healing, prevention or amelioration of therelevant medical condition, or an increase in rate of treatment,healing, prevention or amelioration of such conditions, typicallyproviding a statistically significant improvement in the treated patientpopulation. When referencing an individual active ingredient,administered alone, a therapeutically effective dose refers to thatingredient alone. When referring to a combination, a therapeuticallyeffective dose refers to combined amounts of the active ingredients thatresult in the therapeutic effect, whether administered in combination,including serially or simultaneously. In various embodiments, atherapeutically effective amount of the compound ameliorates one or moresymptoms associated with various neurodegenerative diseases orexcitotoxicity disorders, including but not limited to, bradykinesia,dystonia, psychiatric episodes, including depression, diminished motorfunction, mobility, cognitive ability, or other symptoms of anexcitotoxicity disorder.

“Treatment” refers to prophylactic treatment or therapeutic treatment.In certain embodiments, “treatment” refers to administration of acompound or composition to a subject for therapeutic or prophylacticpurposes.

A “therapeutic” treatment is a treatment administered to a subject whoexhibits signs or symptoms of pathology for the purpose of diminishingor eliminating those signs or symptoms. The signs or symptoms may bebiochemical, cellular, histological, functional or physical, subjectiveor objective.

A “prophylactic” treatment is a treatment administered to a subject whodoes not exhibit signs of a disease or exhibits only early signs of thedisease, for the purpose of decreasing the risk of developing pathology.The compounds or compositions of the disclosure may be given as aprophylactic treatment to reduce the likelihood of developing apathology or to minimize the severity of the pathology, if developed.

“Diagnostic” refers to identifying the presence, extent and/or nature ofa pathologic condition. Diagnostic methods differ in their specificityand selectivity. While a particular diagnostic method may not provide adefinitive diagnosis of a condition, it suffices if the method providesa positive indication that aids in diagnosis.

“Pharmaceutical composition” refers to a composition suitable forpharmaceutical use in a subject animal, including humans and mammals. Invarious embodiments, a pharmaceutical composition comprises atherapeutically effective amount of diffusible small thiol compound,optionally another biologically active agent, and optionally apharmaceutically acceptable excipient, carrier or diluent. In variousembodiments, a pharmaceutical composition comprises a therapeuticallyeffective amount of an agent that inhibits the glutamate/cystinetransporter x_(c) ⁻, and optionally a pharmaceutically acceptableexcipient, carrier or diluent. Optionally, the two agents may be in thesame pharmaceutical composition. In one embodiment, a pharmaceuticalcomposition encompasses a composition comprising the activeingredient(s), and the inert ingredient(s) that make up the carrier, aswell as any product that results, directly or indirectly, fromcombination, complexation or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentdisclosure encompass any composition made by admixing a compound of thedisclosure and a pharmaceutically acceptable excipient, carrier ordiluent.

“Pharmaceutically acceptable carrier” refers to any of the standardpharmaceutical carriers, buffers, and the like, such as a phosphatebuffered saline solution, 5% aqueous solution of dextrose, and emulsions(e.g., an oil/water or water/oil emulsion). Non-limiting examples ofexcipients include adjuvants, binders, fillers, diluents, disintegrants,emulsifying agents, wetting agents, lubricants, glidants, sweeteningagents, flavoring agents, and coloring agents. Suitable pharmaceuticalcarriers, excipients and diluents are described in Remington'sPharmaceutical Sciences, 19th Ed. (Mack Publishing Co., Easton, 1995).Preferred pharmaceutical carriers depend upon the intended mode ofadministration of the active agent. Typical modes of administrationinclude enteral (e.g., oral) or parenteral (e.g., subcutaneous,intramuscular, intravenous or intraperitoneal injection; or topical,transdermal, or transmucosal administration).

A “pharmaceutically acceptable salt” is a salt that can be formulatedinto a compound for pharmaceutical use, including but not limited tometal salts (e.g., sodium, potassium, magnesium, calcium, etc.) andsalts of ammonia or organic amines.

As used herein “pharmaceutically acceptable” or “pharmacologicallyacceptable” salt, ester or other derivative of an active agent comprise,for example, salts, esters or other derivatives refers to a materialthat is not biologically or otherwise undesirable, i.e., the materialmay be administered to an individual without causing any undesirablebiological effects or without interacting in a deleterious manner withany of the components of the composition in which it is contained orwith any components present on or in the body of the individual.

As used herein, the term “unit dosage form” refers to physicallydiscrete units suitable as unitary dosages for human and animalsubjects, each unit containing a predetermined quantity of a compound ofthe disclosure calculated in an amount sufficient to produce the desiredeffect, optionally in association with a pharmaceutically acceptableexcipient, diluent, carrier or vehicle. The specifications for the novelunit dosage forms of the present disclosure depend on the particularcompound employed and the effect to be achieved, and thepharmacodynamics associated with each compound in the host.

As used herein, the term “subject” encompasses mammals. Examples ofmammals include, but are not limited to, any member of the mammalianclass: humans, non-human primates such as chimpanzees, and other apesand monkey species; farm animals such as cattle, horses, sheep, goats,swine; domestic animals such as rabbits, dogs, and cats; laboratoryanimals including rodents, such as rats, mice and guinea pigs, and thelike. The term does not denote a particular age or gender. In variousembodiments the subject is human.

Captons

Captons are small and hydrophobic, with low polar-surface areas,extended plasma residence and minimal protein binding. For example, acapton is <500 daltons, log P >0.8, and exhibits a TPSA <90. Thesecharacteristics allow the captons to cross the blood-brain barrier. Likemany thiols, captons are sensitive to reactive-oxygen species (ROS).Electron transfer neutralizes ROS, simultaneously moving the captonsulfur into higher oxidation states (80-84). Capton sulfinate andsulfonate oxidation products are favored in the extracellular space, orwherever the ratio of ROS-to-thiol is high ((84,85). High ROS-to-thiolratios are created and sustained by glutamate-driven excitotoxic stress,a cause of neurodegeneration (86-90). ROS-neutralizing agents, likecaptons, with the tolerability and pharmacokinetics necessary to bedrugs, are of interest for the clinical management of neurodegenerativediseases.

Captons are also characterized by their similarity to analogs of theneurotransmitter GABA (γ-aminobutyric acid) and the structurally-relatedamino acid, taurine (2-aminoethane-1-sulfonate). Some of these analogsare known to those skilled in the art and some are novel (7-15). Asstated above captons differ from true GABA and taurine analogs by thepresence of a thiol in place of obligate oxoanion functionality,typically a carboxylate (as found in GABA) or a sulfonate (as found intaurine). This substitution will render captons inactive in GABAergic ortaurinergic assays. However, oxidation of the capton thiol to asulfonate uncovers GABAergic or taurinergic function, in some casesgenerating analogs with previously-demonstrated activity (see, forexample, (3R)-piperidine-3-thiol to piperidine-3-sulfonate,piperidine-4-thiol to piperidine-4-sulfonate,(+/−)-trans-1-aminocyclohexane-2-thiol totrans-1-aminocyclohexane-2-sulfonate (TAHS),trans-2-aminocyclopentane-1-thiol totrans-2-aminocyclopentane-1-sulfonate (TAPS),3-amino-2-(4-chlorophenyl)propane-1-thiol to saclophen (7,8),trans-1-aminocyclobutane-3-thiol to trans-1-aminocyclutane-3-sulfonate)(7-15). Unique among aminothiols with molecular weight <300 daltons,captons have GABAergic or taurinergic activity after thiol oxidation.These characteristics differentiate captons from other thiols that mayhave been described previously.

Thiols are often uncharged at physiological pH, giving them highervolumes of distribution (V_(d)) compared to anionic congeners,especially zwitterionic anions paired with positively-charged amines,common amongst known GABAergic (2, 20, 29 119) and calciumchannel-blocking drugs (gabapentinoids (115)). The thiol or selenol willmobilize cysteine by cleaving blood-borne cystine. ROS generated at thesite of neuropathology will then convert the thiol or selenol to asulfinate, sulfonate or seleninate, neutralizing the ROS and generatinga very close anionic analog of the original therapeutic molecule, if notan exact copy of the original therapeutic molecule (often sulfonates).Combining the effects of pre and post-oxidized captons, administrationwill lead to cysteine replenishment, ROS destruction and introduction ofa therapeutic molecule acting on GABA, glutamate, calcium or otherneurologic pathways only at the site of excess ROS production(pathogenic) and in amounts proportional to the actual level of theoxidative stressor. It is hypothesized herein that this effectivelyconstitutes a method for in situ dose-metering by the disease-generatedinsult only in affected areas. It is contemplated that any therapeuticmolecule with a functionally-important anionic moiety, from the groupincluding carboxylate, sulfinate, sulfonate, seleninate, phosphate, orphosphonate, can be administered in the form of a distant analog inwhich a thiol or selenol is substituted for the anionic group.

As described, some oxidized captons, with sulfur oxidation numbers of 2(sulfinate) and 4 (sulfonate), have the necessary functionality to beactive in GABA, taurine, calcium transport and other pathways. Theseoxidized captons (“o-captons” or “ocaptons”) can be analogs of GABA,taurine or the gabapentinoids (17,21,91-114). GABA is the primaryinhibitory neurotransmitter in the CNS. GABA analogs are zwitterions andunable to cross the blood-brain barrier. Captons are not zwitterions andhave been shown to cross the blood-brain barrier or can be reasonablyexpected to cross the blood-brain barrier, after which they can beoxidized to zwitterionic, GABAergic, aminosulfonates. ROS-mediatedcapton conversion is self-limiting, since ROS is consumed in thereaction and localized, and since high ROS levels primarily occur intissues weakened by pathogenic stress. Not to be bound by theory, it ishypothesized that oxidized captons can potentiate GABA signaling in atleast four ways: Direct activation of GABA receptors through orthostericengagement of the GABA binding site; inhibition of GABA reuptake fromthe synapse by GABA transporters, extending receptor exposure to theagonist; inhibition of GABA metabolism by 4-aminobutyrate transaminase;and, finally, inhibition of the pre-synaptic voltage-gated calciumchannel (VGCC), disfavoring release of excitatory neurotransmitters. Therelative levels of glutamate and GABA impacts glutamate excitotoxicity(115,116). GABA receptor activation lowers the sensitivity of neurons toglutamate post-synaptically, reducing excitotoxic stress.

The beneficial effects of oxidized captons are complementary to those oftheir cognate capton thiols. A cognate pair, deriving from a single drugmolecule, offer access to a broad set of therapeutic activities. Someforms of neurodegeneration seem promising candidates for captonintervention, with fundamental contribution to the disease state frommitochondrial dysfunction (e.g., triggered by excess intracellularcalcium), excessive ROS generation, redox-dependent protein aggregationand hyperactivation of glutamate signalling pathways (countered byGABAergic and taurinergic activity).

PCT/US2016/040637 discloses that certain of the compounds contemplatedtherein may be useful to treat excitotoxicity disorders that result fromexcess glutamate being secreted by various cells, including immune cellsand neurons, in the brain. PCT/US2016/040637 describes that certainagents are capable of inhibiting glutamate-induced excitotoxicity inSt-HdhQ^(111/111) cells. The assay used in PCT/US2016/040637 measurescell survival after glutamate induced excitotoxicity. The assay cannot,however, measure the effect of the compounds on neurotransmissionincluding GABAergic, glutamatergic or calcium channel modulatingeffects.

In various embodiments, the capton can be a compound having thestructure of Formula (I) or a disulfide thereof:

Formula I:

wherein:

wherein:

R¹ and R² are independently selected from the group consisting of H andC₁₋₅alkyl; or

R¹ and R², taken together with the carbon atom to which they areattached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

R³ and R⁴ are independently selected from the group consisting of H andC₁₋₅alkyl; or

R³ and R⁴, taken together with the carbon atom to which they areattached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

G is selected from the group consisting of —NR⁵R⁶ and —CR⁷R⁸NR⁵R⁶;

R⁵ and R⁶ are independently selected from the group consisting of H andC₁₋₅alkyl; or

R⁵ and R⁶, taken together with the nitrogen atom to which they areattached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring;

R⁷ and R⁸ are independently selected from the group consisting of H andC₁₋₅alkyl; or

R⁷ and R⁸, taken together with the carbon atom to which they areattached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

R² and R⁶, taken together with the atoms to which they are attached,optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclicring;

R⁴ and R⁶, taken together with the atoms to which they are attached,optionally form a 4-, 5-, 6-, 7-, 8-, 9-, or 10-membered heterocyclicring;

R⁴ and R⁸, taken together with the atoms to which they are attached,optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

R² and R⁸, taken together with the atoms to which they are attached,optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

R² and R⁴, taken together with the atoms to which they are attached,optionally form a 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic ring;

wherein a C₁₋₅ alkyl moiety, wherever it occurs, can optionally comprisea double bond; and

wherein a C₁₋₅ alkyl, 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic orheterocyclic moiety, wherever it occurs, can optionally be substitutedwith from one to three substituents which are not further substitutedand which are independently selected from the group consisting of —CN,thio, halo, hydroxy, C₆₋₁₀ aryl, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₆cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3heteroatoms selected from O, N, and S, CO₂H, CO₂C₁₋₆alkyl,C(O)C₁₋₆alkyl, CO₂NH₂, CO₂NHC₁₋₆alkyl, and —CO₂N(C₁₋₆alkyl)₂.

In some cases, when G is —NH₂, at least one of R¹, R², R³, and R⁴ isother than H.

In some cases, R⁵ and R⁶ are independently selected from the groupconsisting of H, methyl, and ethyl. In some cases, R⁵ and R⁶, takentogether with the nitrogen atom to which they are attached, form a5-membered heterocyclic ring.

In some cases, wherein R⁴ is methyl and/or R³ is methyl. In some cases,R³ and R⁴, taken together with the carbon atom to which they areattached, form a 3-membered carbocyclic ring.

In some cases, R² is methyl and/or R¹ is methyl. In some cases, R¹ andR², taken together with the carbon atom to which they are attached, forma 3-membered carbocyclic ring.

In some cases, G is —CR⁷R⁸NR⁵R⁶, and R² and R⁶, taken together with theatoms to which they are attached, form a 6-membered heterocyclic ring.In some cases, R⁵ is methyl.

In some cases, G is —NR⁵R⁶, and R² and R⁶, taken together with the atomsto which they are attached, form a 4- or 6-membered heterocyclic ring.In some cases, R⁵ is H.

In some cases, R⁷ and R⁸ are both H.

In some cases, SH is replaced by SeH.

A compound of Formula I includes, but is not limited to, the followingcompounds:

and disulfides thereof.

In some cases, the compound of Formula I has the structure of FormulaIa, Ib, Ic, Id, or Ie:

In some cases, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independentlyselected from the group consisting of H and C₁₋₅alkyl. In some cases,R¹, R², R³, R⁴, R⁵, R⁶, R⁷, and R⁸ are independently selected from thegroup consisting of H and methyl.

In some cases, the capton can be a compound having the structure ofFormula II, or a disulfide thereof:

HS-L-NR⁹R¹⁰  (II), wherein:

L is a hydrocarbon linking group;

R⁹ and R¹⁰ are independently selected from the group consisting of H,C₁₋₅alkyl, and CO(C₁₋₅alkyl); or

R⁹ and R¹⁰, taken together with the nitrogen atom to which they areattached, form a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic ring;

wherein a C₁₋₅ alkyl moiety, wherever it occurs, can optionally comprisea double bond; and

wherein a C₁₋₅ alkyl, 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic orheterocyclic moiety, wherever it occurs, can optionally be substitutedwith from one to three substituents which are not further substitutedand which are independently selected from the group consisting of —CN,thio, halo, hydroxy, C₆₋₁₀ aryl, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₆cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3heteroatoms selected from O, N, and S, CO₂H, CO₂C₁₋₆alkyl,C(O)C₁₋₆alkyl, CO₂NH₂, CO₂NHC₁₋₆alkyl, and —CO₂N(C₁₋₆alkyl)₂.

In some cases, the compound of Formula II is not cysteamine.

In some cases, L is a 3-, 4-, 5-, 6-, 7-, or 8-membered cycloalkyl ringor a 6-membered aryl ring. In some cases, L is C₁₋₆alkyl. In some cases,L is substituted with one to four groups selected from halo, C₁₋₆alkyl,C₃₋₆cycloalkyl, and —CO₂(C₁₋₆alkyl).

In some cases, the capton is a compound having the structure of Formula(III):

wherein:

A is a 3 to 8 membered heterocyclic ring containing one N atom;

n is 0, 1, 2, or 3; and

wherein a 3-, 4-, 5-, 6-, 7-, or 8-membered heterocyclic moiety,wherever it occurs, can optionally be substituted with from one to threesubstituents which are not further substituted and which areindependently selected from the group consisting of —CN, thio, halo,hydroxy, C₆₋₁₀ aryl, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₃₋₆cycloalkyl, 5- or6-membered heterocycloalkyl containing 1-3 heteroatoms selected from O,N, and S, CO₂H, CO₂C₁₋₆alkyl, C(O)C₁₋₆alkyl, CO₂NH₂, CO₂NHC₁₋₆alkyl, and—CO₂N(C₁₋₆alkyl)₂.

In some cases, A is a 3-, 4-, 5-, 6-, 7-, or 8-membered monocyclicheterocycloalkyl ring, a 6-, 7-, or 8-membered bicyclic heterocycloalkylring, or a 5- or 6-membered heteroaryl ring.

In some cases, the compound of formula III has a structure IIIa:

wherein R¹¹ is selected from the group consisting of H and C₁₋₅alkyl.

In some cases, A is substituted with one to four groups selected fromhalo, C₁₋₅alkyl, C₃₋₅cycloalkyl, and —CO₂(C₁₋₅alkyl).

Compounds contemplated herein also include, but are not limited to thoseset out in FIGS. 1 and 2.

Specific compounds contemplated include compounds in the followingTable.

The compound can be a compound as listed in Table A, or apharmaceutically acceptable salt thereof.

TABLE A Com- pound No. Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42

43

44

45

46

47

48

49

50

51

52

53

54

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

73

74

75

76

77

78

79

80

81

82

83

84

85

86

87

88

89

90

91

92

93

94

95

96

97

98

99

100

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117

118

119

120

121

122

123

124

125

126

127

128

129

130

131

132

133

134

135

136

137

138

139

140

141

142

143

144

145

146

147

148

149

150

151

152

153

154

155

156

157

158

159

160

161

162

163

164

165

166

167

168

169

170

171

172

173

174

175

176

177

178

179

181

182

183

184

185

186

187

188

189

190

191

192

193

194

196

197

198

199

200

201

202

203

204

205

206

207

208

209

210

211

212

213

214

215

216

217

218

219

220

221

222

223

224

225

226

Methods of Use

It is contemplated herein that captons are useful to counter the effectsof ROS in the brain of subjects having a neurodegenerative disease, aswell as provide neuroprotection for, or prevent or ameliorate futureneurodegeneration mediated by, activity in which trauma to the brain mayoccur, e.g., as in traumatic brain injury and chronic traumaticencephalopathy.

TBI and CTE

Traumatic brain injury (TBI) is an acute condition, often caused byblunt force trauma to the head. Damage results from longitudinal andshearing forces on neurons and, particularly, long axonal tractsthroughout the brain. These forces can lead to gross structuralcompromise and cell death. Dead neurons release large amounts ofglutamate into the extracellular space, along with the rest of theircontents. Elevated glutamate causes persistent activation of glutamatereceptors with uncontrolled influx of calcium and other cations (90).Systems that reestablish ionic balance are overwhelmed, consumingconsiderable amounts of ATP in the process. Excess calcium also leads tomitochondrial depolarization, forcing increased flux through theelectron-transport chain and its inevitable consequence,reaction-oxygen-species (ROS). Toxic levels of ROS deplete cellularantioxidant systems necessary for survival (117-120). Uncontrolledcalcium levels and depolarization of membrane potentials causeorganellar dysfunction, most critically the release of mitochondrialcytochrome C and apoptotic cell-death (62,121-124). Capton mechanismsbolster endogenous antioxidant pools, deplete cells of ROS and reduceneuronal sensitivity to glutamate as previously described in thisapplication. Captons may be a useful way to address the acute phase ofTBI.

Acute TBI may be followed by a sustained, subacute, but progressive,secondary phase. The slower phase resembles other progressiveneurodegenerative conditions, like amyotrophic lateral sclerosis (ALS),Alzheimer's disease and fronto-temporal dementia (FTD). Multiple impactssustain the secondary phase and result in a condition known as chronictraumatic encephalopathy (CTE). CTE has a high prevalence amongprofessional athletes and combat veterans, who often suffer repetitive,concussive brain trauma (52, 117, 125). Glutamate hyperexcitation,calcium imbalance and elevated ROS, which underlie acute TBI, continueto figure prominently in CTE pathology, with a significant additionalcontribution from protein aggregation (50,52,126,127). Intracellular,pathogenic, protein aggregates, observed in most neurodegenerativediseases, are a hallmark of CTE. CTE aggregates are specificallyenriched in tau and TDP-43, both proteins that can adopt pathogenicconformations that seed further misfolding and are, consequently,transmissible. Aggregation of tau and TDP-43 require ROS, withinter-protein oxidative disulfide formation a necessary component(44,54,56,128). Captons neutralize ROS and, as stable thiolates,efficiently cleave disulfides. Insoluble TDP-43 has been shown to besolubilized by thiol agents, potentially reversing aggregates (44).Therefore, captons may be potentially useful in the treatment of CTE,the consequence of chronic TBI.

Excitotoxicity Disorders

Excitotoxicity disorders result from excessive glutamate release in thecentral nervous system resulting in glutamate toxicity to thesurrounding cells. Glutathione is a tripeptide made ofglutamate-cysteine-glycine and is an important buffer of oxidativestress in the brain. GSH is synthesized from extracellular cystine takenup via the glutamate:cystine exchange transporter and converted back totwo cysteine molecules within the reductive environment of the cell. Thecysteines can then be incorporated into glutathione. The x_(c) ⁻transporter, also called the antiporter, or xCT, is a Nat-independentcystine-glutamate exchange system that takes up cystine and exportsglutamate from the cell in a 1:1 exchange ratio (33).

Glutathione-based antioxidant systems exhibit redundancy with a secondsystem that includes such components as thioredoxin, thioredoxinreductase, TRP14, peroxiredoxin, nicotinamide nucleotidetranshydrogenase and reduced nicotinamide adenine dinucleotidecofactors. Sulfur amino acids, incorporated into redox-controllingproteins, are also a key feature of this second anti-oxidant network,which, therefore, also depends on xCT.

Pharmacologically, application of small thiol molecules has beendemonstrated to rescue deficits in antioxidant capacity, includingcomplete loss of the GSH-based system. Contemplated herein are methodsof treating an excitotoxicity disorder using a compound as disclosedherein. Exemplary excitotoxicity disorders contemplated herein include,but are not limited to, spinal cord injury, stroke or other ischemia,traumatic brain injury, chronic traumatic encephalopathy (CTE), hearingloss, neurodegenerative diseases, multiple sclerosis, Alzheimer'sdisease, amyotrophic lateral sclerosis (ALS), Parkinson's disease,Huntington's disease, concussion, epilepsy and CNS depressant-withdrawalsyndrome.

Huntington's Disease

Huntington's disease (HD) is an adult-onset neurodegenerative disorderfor which treatment strategies have helped address certain symptoms ofHD, but remain ineffective at truly treating the disease. HD is anautosomal dominant genetic disorder with a prevalence of about 5-10 per100,000 in the Caucasian population. Clinical symptoms include choreaand behavioral disorders but the most problematic features of thedisease are slowly progressive motor dysfunction and impaired cognition(Ha et al., Curr Opin Neurol 25(4):491-8, 2012). The pathology of HD ischaracterized by the presence of neuritic and intranuclear inclusions inneurons and relatively selective neural loss in the striatum and thedeeper layers of the cerebral cortex. HD is caused by aCytosine-Adenine-Guanine (CAG) triplet repeat expansion in the firstexon of the HTT gene leading to an expanded polyglutamine stretch in thehuntingtin protein (The Huntington's Disease Collaborative ResearchGroup. A novel gene containing a trinucleotide repeat that is expandedand unstable on Huntington's disease chromosomes. Cell 72(6):971-83,1993). HD develops when the polyglutamine expansion exceeds 35, a pointthat enlarges the polyglutamine stretch past a critical threshold thatpredisposes to aggregation. There is an inverse correlation between thenumber of CAG and the age at onset (Andrew et al., Nat Genet4(4):398-403, 1993). Mutant huntingtin has been implicated in thedisruption of many cellular processes, including protein clearance,protein—protein interaction, mitochondrial function, axonal trafficking,N-methyl-D-aspartate receptor activation, gene transcription andpost-translational modification (Zuccato et al., Physiol Rev 2010;90(3):905-81, Labbadia et al., Trends Biochem Sci 2013; 38(8):378-85).Although mutant huntingtin has a widespread distribution in neuronal andnon-neuronal tissues, the medium spiny GABAergic neurons of the striatumexhibit the most pronounced vulnerability (Labbadia et al., TrendsBiochem Sci 2013; 38(8):378-85).

Huntington's Disease is often defined or characterized by onset ofsymptoms and progression of decline in motor and neurological function.HD can be broken into five stages: Patients with early HD (stages 1 and2) have increasing concerns about cognitive issues, and these concernsremain constant during moderate/intermediate HD (stages 3 and 4).Patients with late-stage or advanced HD (stage 5) have a lack ofcognitive ability (Ho et al., Clin Genet. September 2011;80(3):235-239).

Progression of the stages can be observed as follows: Early Stage (stage1), in which the person is diagnosed as having HD and can function fullyboth at home and work. Early-Intermediate Stage (stage 2), in which theperson remains employable but at diminished capacity and can managetheir daily affairs, albeit with some difficulty. Late-IntermediateStage (stage 3), in which the person can no longer work and/or managehousehold responsibilities. At this stage, the person may need help tohandle daily financial and other affairs. Early-Advanced Stage patients(stage 4) are no longer independent in daily activities but are able tolive at home, supported by family or professional caregivers. In theAdvanced Stage (stage 5), the person requires complete support in dailyactivities and professional nursing care. Patients with HD usually dieabout 15 to 20 years after their symptoms first appear.

In intermediate stages, as the disease progresses, the initial motorsymptoms will gradually develop into more obvious involuntary movementssuch as jerking and twitching of the head, neck, arms and legs. Thesemovements may interfere with walking, speaking and swallowing. People atthis stage of Huntington's often look as if they're drunk: they staggerwhen they walk and their speech is slurred. They have increasingdifficulty working or managing a household, but can still deal with mostactivities of daily living. The advanced stages of HD typically involvefewer involuntary movements and more rigidity. Patients in these stagesof HD can no longer manage the activities of daily living. Difficultieswith swallowing, communication and weight loss are common in theadvanced stage.

Chorea is the most common movement disorder seen in HD. Initially, mildchorea resembles fidgetiness. As the disease progresses, choreagradually moves towards and is replaced by dystonia and parkinsonianfeatures, such as bradykinesia, rigidity, and postural instability. Inadvanced disease, patients develop an akinetic-rigid syndrome, withminimal or no chorea, as well as spasticity, clonus, and extensorplantar responses. Dysarthria and dysphagia are common. Abnormal eyemovements, tics and myoclonus may be seen in patients with HD. JuvenileHD (Westphal variant), defined as having an age of onset of younger than20 years, is characterized by parkinsonian features, dystonia,long-tract signs, dementia, epilepsy, and mild or even absent chorea.

Cognitive decline is also characteristic of HD, and the rate ofprogression can vary among individual patients. Dementia and thepsychiatric features of HD are often the earliest of functionalimpairment. Dementia syndrome associated with HD includes early onsetbehavioral changes, such as irritability, untidiness, and loss ofinterest, followed by slowing of cognition, impairment of intellectualfunction, and memory disturbances. This pattern corresponds well to thesyndrome of subcortical dementia, and it has been suggested to reflectdysfunction of frontal-subcortical neuronal circuitry.

Early stages of HD are characterized by deficits in short-term memory,followed by motor dysfunction and a variety of cognitive changes in theintermediate stages of dementia (Loy et al., PLoS Curr. 2013; 5: Cleretde Langavant et al., PLoS One. 2013; 8(4):e61676). These deficitsinclude diminished verbal fluency, problems with attention, executivefunction, visuospatial processing, and abstract reasoning. Languageskills become affected in the final stages of the illness, resulting inmarked word-retrieval deficiency.

HD can also manifest in behavioral disorders, including depression, witha small percentage of patients experiencing bouts of maniacharacteristic of bipolar disorder, an increased rate of suicide, andpsychosis, obsessive-compulsive symptoms, sexual and sleep disorders,and changes in personality.

Parkinson's Disease

Parkinson's disease (PD) is a complex neurodegenerative disorderinvolving the predominant loss of dopaminergic neurons in the substantianigra pars compacta (SNc), subsequent decay of the nigrostriatal tractand associated movement anomalies such as rigidity, bradykinesia andtremor. Pathological features associated with substantial nigradegeneration include mitochondrial abnormalities, loss of antioxidantenzyme systems and reduced glutathione (GSH) levels (Bharath et al.,Biochem Pharmacol. 64:1037-48, 2002).

Stages of a Parkinson's disease patient is described by Hoehn and Yahrin following five distinct stages depending on the symptoms (Hoehn M M,Yahr M D, Parkinsonism: onset, progression and mortality. Neurology1967, 17:427-42). Stage I: (mild or early disease): symptoms affect onlyone side of the body. Stage II: both sides of the body are affected, butposture remains normal. Stage III: (moderate disease): both sides of thebody are affected, and there is mild imbalance during standing orwalking, however, the person remains independent. Stage IV: (advanceddisease): both sides of the body are affected, and there is disablinginstability while standing or walking. The person in this stage requiressubstantial help. Stage V: severe, fully developed disease is present.The person is restricted to a bed or chair.

Ischemia

Ischemia refers to a condition resulting from a decrease or lack ofblood flow and oxygen to a part of the body such as the brain, heart, orother tissue. Ischemic injury refers generally to the damage to a tissuethat is distal or otherwise effected by the loss of blood flow andoxygen. Ischemic injury is often a result of the lack of oxygen andfluids, but also includes inflammatory cascades. For example, ischemiaand ischemic injury can occur as a result of cardiac, pulmonary or braininjury, organ transplantation or surgical procedure, or a disease ordisorder.

Acute ischemia is most often recognized in strokes and cardiac damage.However, there are a number of disorders and injuries that causeischemic events leading to cell death and tissue damage. Strokes,cerebrovascular events and cardio vascular events are the result of anacute obstruction of cerebral or cardiac blood flow to a region of thebrain or heart, respectively. There are approximately 500,000 cases ofstroke each year in the United States, of which 30% are fatal, and hencestroke is the third leading cause of death in the United States.Approximately 80% of strokes are “ischemic” and result from an acuteocclusion of a cerebral artery with resultant reduction in blood flow.The remainder are “hemorrhagic”, which are due to rupture of a cerebralartery with hemorrhage into brain tissue and consequent obstruction ofblood flow due to lack of flow in the distal region of the rupturedvessel and local tissue compression, creating ischemia.

Stroke commonly affects individuals older than 65 years. In 1996, theFDA approved the use of tissue plasminogen activator (tPA) as therapyfor acute ischemic stroke, based on a limited number of controlledtrials. Approximately twenty percent of strokes may involve bleedingwithin the brain, which damages nearby brain tissue (for example, ahemorrhagic stroke). Hemorrhagic stroke occurs when a blood vesselbursts inside the brain. The brain is sensitive to bleeding and damagecan occur rapidly, either because of the presence of the blood itself,or because the fluid increases pressure on the brain and harms it bypressing it against the skull. The surrounding tissues of the brainresist the expansion of the bleeding, which is finally contained byforming a mass (for example, an intracerebral hematoma). Both swellingand hematoma will compress and displace normal brain tissue.

There appears to be a correlation between an early reduction inglutathione levels in ischemia and the activation of lipooxygenases bythe inflammatory cascade, which may play a role in ischemia-inducednerve cell loss. In vitro cell culture assays have shown that inhibitorsof lipoxygenase 12-LOX block glutamate-induced cell death, and both 5-and 12-LOX inhibitors block ischemic injury in hippocampal slicecultures.

Alzheimer's Disease

Alzheimer's disease (AD) is characterized by chronic, progressiveneurodegeneration. Neurodegeneration in AD involves earlysynaptotoxicity, neurotransmitter disturbances, accumulation ofextracellular β-amyloid (Aβ) deposits and intracellular neurofibrils,and gliosis and at later stages loss of neurons and associated brainatrophy (Danysz et al., Br J Pharmacol. 167:324-352, 2012). Earlystudies indicated AR peptides may have the ability to enhance glutamatetoxicity in human cerebral cortical cell cultures (Mattson et al., JNeurosci. 12:376-389, 1992; Li et al., J Neurosci. 31(18):6627-38,2011).

It is contemplated herein that administration of a small thiolcomposition as described herein in combination with an agent thatinhibits the glutamate/cysteine antiporter can alleviate or treat one ormore symptoms associated with excitotoxicity disease or disorder. Suchsymptoms, include but are not limited to, one or more motor skills,cognitive function, dystonia, chorea, psychiatric symptoms such asdepression, brain and striatal atrophies, and neuronal dysfunction.

It is contemplated that the administration results in a slowerprogression of total motor score compared to a subject not receivingthiol composition and inhibitor. In some embodiments, the slowerprogression is a result in improvement in one or more motor scoresselected from the group consisting of chorea subscore, balance and gaitsubscore, hand movements subscore, eye movement subscore, maximaldystonia subscore and bradykinesia assessment.

Additional indicia of a slower decline in symptoms of HD are measuredusing change from baseline in one or more of the following parameters:using standardized tests for (i) functional assessment (e.g., UHDRSTotal Functional Capacity, LPAS, Independence Scale); (ii)neuropsychological assessment (e.g., UHDRS Cognitive Assessment, MattisDementia Rating Scale, Trail Making Test A and B, Figure CancellationTest, Hopkins Verbal Learning Test, Articulation Speed Test); (iii)psychiatric assessment (UHDRS Behavioral Assessment, Montgomery andAsberg Depression Rating Scale) and (iv) cognitive assessment (e.g.,Dementia Outcomes Measurement Suite (DOMS)).

In certain embodiments, alteration in one or more symptoms in patientsreceiving small diffusible thiol composition that is oxidized to a asulfinic acid or sulfonic acid after crossing the blood brain barrier isshown to be beneficial by at least 10%, 20%, 25%, 30%, 35%, 40%, 45%,50%, 55%, 60%, 65%, 70%, 75% or more compared to baseline assessment ofthe symptom. In certain embodiments, the rate of progression or declinein total motor score is slowed, by at least 20%, 25%, 30%, 35%, 40%,45%, 50%, 55%, 60%, 65%, 70%, 75% or more. Measurement may be performedusing techniques known in the art, e.g., the Unified Huntington DiseaseRating Scale (UHDRS), Bradykinesia Ratings Scale, and Lindop Parkinson'sAssessment Scale (LPAS).

In certain embodiments, the symptoms are measured at 3 months, 6 months,12 months, 18 months or 2 years or more after administration.

Provided herein is a method of treating a neurological disease ordisorder comprising administering a small thiol compound (e.g., <500daltons, log P >0.8, TPSA <90) that can be oxidized by reactive-oxygenspecies after crossing the blood-brain barrier to a sulfinic or sulfonicacid and wherein the oxidized compound possesses GABAergic, calciumchannel inhibiting, glutamatergic or other neurologic activity. Alsoprovided is a method of treating an excitotoxicity disorder comprisingadministering the small thiol compound; a method of treating aneurological disease or disorder characterized by aggregation of TDP-43comprising administering the small thiol compound; a method of treatinga neurological disease or disorder characterized by aggregation ofsuperoxide dismutase 1 (SOD1) protein comprising administering the smallthiol compound. In various embodiments, the disease is furthercharacterized by aggregation of tau protein.

Exemplary neurodegenerative or excitotoxicity disorders includeamyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration,traumatic brain injury, chronic traumatic encephalopathy (CTE),Alzheimer's disease, ischemia or epilepsy. Also contemplated is familialor sporadic ALS.

The disclosure also provides a method for slowing the progression ofbrain and striatal atrophies and/or treating dystonia in a subjectsuffering from an excitotoxicity disease comprising administering to asubject in need thereof the small thiol composition that is oxidized toa sulfinic acid or sulfonic acid after crossing the blood brain barrier.

Also provided is a method for treating or ameliorating glutamatetoxicity in a subject comprising administering an effective amount of asmall thiol compound (<500 daltons, log P >0.8, TPSA <90) that can beoxidized by reactive-oxygen species after crossing the blood-brainbarrier to a sulfinic or sulfonic acid and where the oxidized compoundpossesses GABAergic, calcium channel inhibiting, glutamatergic or otherneurologic activity. In various embodiments, the administration reducesneuronal glutamate toxicity.

It is contemplated that the small diffusible thiol compound useful inany one of the methods is a capton as described herein. Exemplarycaptons are set out in FIGS. 1 and 2, in Formulas I, II and III, anddescribed further in the detailed description.

Further provided is a method for slowing the degeneration of neurons ina subject, or a method for treating or ameliorating glutamate toxicityin a subject, comprising administering an effective amount of a compoundof Formula I, II or III or a small thiol compound (<500 daltons, logP >0.8, TPSA <90) that can be oxidized by reactive-oxygen species aftercrossing the blood-brain barrier to a sulfinic or sulfonic acid andwhere the oxidized compound possesses GABAergic, calcium channelinhibiting, glutamatergic or other neurologic activity.

In various embodiments, the thiol administration improves one or moresymptoms of a neurodegenerative disorder or excitotoxicity disorder.Exemplary symptoms include diminished motor function, mobility,cognitive ability, or other symptoms of an excitotoxicity disorder.

The small thiol compound also exhibits neuroprotective effects in aneuronal tissue-culture model of excitotoxicity, oxidative stress,glutamate overstimulation, elevated intracellular calcium, GABA receptorfunction, mitochondrial stress or the consequences of these phenomena.

In various embodiments, the small thiol compound or its oxidizedequivalent improves cell-viability, reduces calcium transport, relievesmitochondrial stress, enhances mitophagy, modulates GABA activity,modulates glutamate activity or inhibits voltage-gated calcium channelactivity in a subject.

It is contemplated that the small thiol or capton provides relief in therecited disorders by acting to i) reduce levels of ROS in the CNS; ii)increase intracellular cysteine and the sum of all intracellularlow-molecular weight thiols; iii) reduce weak metal-protein interactionsthrough binding of unchaperoned metal-ions; and/or iv) reduceintracellular protein aggregation that is dependent on oxidation ofcysteine.

Pharmaceutical Formulations

The disclosure provides for use of small diffusible thiol compositionthat is oxidized to a sulfinic acid or sulfonic acid after crossing theblood brain barrier in the treatment of neurodegenerative disorders,including excitotoxicity diseases or disorders, such as Huntington'sDisease, Parkinson's disease, ischemia, or Alzheimer's disease (e.g., toslow or improve motor skills, cognitive function and promote neuronalregeneration), amyotrophic lateral sclerosis (ALS), familial or sporadicALS, frontotemporal lobar degeneration, chronic traumatic encephalopathy(CTE), or traumatic brain injury. To administer a small diffusible thiolcomposition that is oxidized to a sulfinic acid or sulfonic acid aftercrossing the blood brain barrier to patients or test animals, it ispreferable to formulate the therapeutics in a composition comprising oneor more pharmaceutically acceptable carriers. Pharmaceutically orpharmacologically acceptable carriers or vehicles refer to molecularentities and compositions that do not produce allergic, or other adversereactions when administered using routes well-known in the art, asdescribed below, or are approved by the U.S. Food and DrugAdministration or a counterpart foreign regulatory authority as anacceptable additive to orally or parenterally administeredpharmaceuticals. Pharmaceutically acceptable carriers includeany-and-all clinically useful solvents, dispersion media, coatings,antibacterial and antifungal agents, isotonic and absorption delayingagents and the like.

Pharmaceutical carriers include pharmaceutically acceptable salts,particularly where a basic or acidic group is present in a compound. Forexample, when an acidic substituent, such as —COOH, is present, theammonium, sodium, potassium, calcium and the like salts, arecontemplated for administration. Additionally, where an acid group ispresent, pharmaceutically acceptable esters of the compound (e.g.,methyl, tert-butyl, pivaloyloxymethyl, succinyl, and the like) arecontemplated as preferred forms of the compounds, such esters beingknown in the art for modifying solubility and/or hydrolysischaracteristics for use as sustained release or prodrug formulations.

When a basic group (such as amino or a basic heteroaryl radical, such aspyridyl) is present, then an acidic salt, such as hydrochloride,hydrobromide, acetate, maleate, pamoate, phosphate, methanesulfonate,p-toluenesulfonate, and the like, is contemplated as a form foradministration.

In addition, compounds may form solvates with water or common organicsolvents. Such solvates are contemplated as well.

The small diffusible thiol composition that is oxidized to a sulfinicacid or sulfonic acid after crossing the blood brain barrier may beadministered orally, parenterally, transocularly, intranasally,transdermally, transmucosally, by inhalation spray, vaginally, rectally,or by intracranial injection. The term parenteral as used hereinincludes subcutaneous injections, intravenous, intramuscular,intracisternal injection, or infusion techniques. Administration byintravenous, intradermal, intramusclar, intramammary, intraperitoneal,intrathecal, retrobulbar, intrapulmonary injection and or surgicalimplantation at a particular site is contemplated as well. Generally,compositions for administration by any of the above methods areessentially free of pyrogens, as well as other impurities that could beharmful to the recipient. Further, compositions for administrationparenterally are sterile.

Pharmaceutical compositions of the disclosure containing a smalldiffusible thiol composition that is oxidized to a sulfinic acid orsulfonic acid after crossing the blood brain barrier as an activeingredient may contain pharmaceutically acceptable carriers or additivesdepending on the route of administration. Examples of such carriers oradditives include water, a pharmaceutically acceptable organic solvent,collagen, polyvinyl alcohol, polyvinylpyrrolidone, a carboxyvinylpolymer, carboxymethylcellulose sodium, polyacrylic sodium, sodiumalginate, water-soluble dextran, carboxymethyl starch sodium, pectin,methyl cellulose, ethyl cellulose, xanthan gum, gum Arabic, casein,gelatin, agar, diglycerin, glycerin, propylene glycol, polyethyleneglycol, Vaseline, paraffin, stearyl alcohol, stearic acid, human serumalbumin (HSA), mannitol, sorbitol, lactose, a pharmaceuticallyacceptable surfactant and the like. Additives used are chosen from, butnot limited to, the above or combinations thereof, as appropriate,depending on the dosage form of the disclosure.

Formulation of the pharmaceutical composition will vary according to theroute of administration selected (e.g., solution, emulsion). Anappropriate composition comprising the small thiol or capton compositionto be administered can be prepared in a physiologically acceptablevehicle or carrier. For solutions or emulsions, suitable carriersinclude, for example, aqueous or alcoholic/aqueous solutions, emulsionsor suspensions, including saline and buffered media. Parenteral vehiclescan include sodium chloride solution, Ringer's dextrose, dextrose andsodium chloride, lactated Ringer's or fixed oils. Intravenous vehiclescan include various additives, preservatives, or fluid, nutrient orelectrolyte replenishers.

A variety of aqueous carriers, e.g., water, buffered water, 0.4% saline,0.3% glycine, or aqueous suspensions may contain the active compound inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

In some embodiments, the small diffusible thiol composition that isoxidized to a sulfinic acid or sulfonic acid after crossing the bloodbrain barrier disclosed herein can be lyophilized for storage andreconstituted in a suitable carrier prior to use. Any suitablelyophilization and reconstitution techniques can be employed. It isappreciated by those skilled in the art that lyophilization andreconstitution can lead to varying degrees of activity loss and that uselevels may have to be adjusted to compensate.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active compound inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

In one embodiment, the disclosure provides use of an enterically coatedsmall diffusible thiol composition that is oxidized to a sulfonate uponcrossing the blood brain barrier. Enteric coatings prolong release untilthe product reaches the intestinal tract, typically the small intestine.Because of the enteric coatings, delivery to the small intestine isimproved thereby improving uptake of the active ingredient whilereducing gastric side effects.

In some embodiments, the coating material is selected such that thetherapeutically active agent is released when the dosage form reachesthe small intestine or a region in which the pH is greater than pH 4.5.In various embodiments, the formulation releases at a pH of about 4.5 to6.5, 4.5 to 5.5, 5.5 to 6.5 or about pH 4.5, 5.0, 5.5, 6.0 or 6.5.

The coating may be a pH-sensitive material, which remain intact in thelower pH environs of the stomach, but which disintegrate or dissolve atthe pH commonly found in the small intestine of the patient. Forexample, the enteric coating material begins to dissolve in an aqueoussolution at pH between about 4.5 to about 5.5. For example, pH-sensitivematerials will not undergo significant dissolution until the dosage formhas emptied from the stomach. The pH of the small intestine graduallyincreases from about 4.5 to about 6.5 in the duodenal bulb to about 7.2in the distal portions of the small intestine. In order to providepredictable dissolution corresponding to the small intestine transittime of about 3 hours (e.g., 2-3 hours) and permit reproducible releasetherein, the coating should begin to dissolve at the pH range within thesmall intestine. Therefore, the amount of enteric polymer coating shouldbe sufficient to substantially dissolved during the approximatethree-hour transit time within the small intestine, such as the proximaland mid-intestine.

Dosing and Administration

The small diffusible thiol composition that is oxidized to a sulfinicacid or sulfonic acid after crossing the blood brain barrier isadministered in a therapeutically effective amount; typically, in unitdosage form. The amount of product administered is, of course, dependenton the age, weight, and general condition of the patient, the severityof the condition being treated, and the judgment of theprescribing-physician. Suitable therapeutic amounts will be known tothose skilled in the art and/or are described in the pertinent referencetexts and literature. As a comparison, current non-enterically coateddoses of cysteamine are about 1.35 g/m² body surface area and areadministered 4-5 times per day (Levtchenko et al., Pediatr Nephrol.21:110-113, 2006). In one aspect, the dose of therapeutic isadministered either one time per day or multiple times per day.

The small diffusible thiol composition may be administered less thanfour time per day, e.g., one, two or three times per day. In variousembodiments, the total daily dose of small thiol composition or apharmaceutically acceptable salt thereof for treatment of a disease ordisorder described herein is between 200 to 1000, 500 to 2000 mg, 750 to1750 mg, 1000 to 1500 mg, or may range between any two of the foregoingvalues. In various embodiments, the total daily dose of small diffusiblethiol or a pharmaceutically acceptable salt thereof, is 200, 300, 400,500, 600, 700, 800, 900, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700,1800, 1900 or 2000 mg per day. It is contemplated that any of theforegoing doses is administered twice daily. It is further contemplatedthat any of the foregoing doses is administered in two equal dosesdaily. Optionally, the daily dose is administered in three doses.

In some embodiments, an effective dosage of small thiol composition maybe within the range of 0.01 mg to 1000 mg per kg (mg/kg) of body weightper day. In some embodiments, the small diffusible thiol composition orpharmaceutically acceptable salt thereof is administered at a daily doseranging from about 1 to about 50 mg/kg/day, or from about 10 mg/kg toabout 250 mg/kg, or from about 100 mg/kg to about 250 mg/kg, or fromabout 60 mg/kg to about 100 mg/kg or from about 50 mg/kg to about 90mg/kg, or from about 30 mg/kg to about 80 mg/kg, or from about 20 mg/kgto about 60 mg/kg, or from about 10 mg/kg to about 50 mg/kg, or fromabout 15 to about 25 mg/kg, or from about 15 to about 20 mg/kg or fromabout 10 to about 20 mg/kg. Further, the effective dose may be 0.5mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, 20 mg/kg/25 mg/kg, 30mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 70mg/kg, 75 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg,175 mg/kg, 200 mg/kg, 225 mg/kg, 250 mg/kg, 275 mg/kg, 300 mg/kg, 325mg/kg, 350 mg/kg, 375 mg/kg, 400 mg/kg, 425 mg/kg, 450 mg/kg, 475 mg/kg,500 mg/kg, 525 mg/kg, 550 mg/kg, 575 mg/kg, 600 mg/kg, 625 mg/kg, 650mg/kg, 675 mg/kg, 700 mg/kg, 725 mg/kg, 750 mg/kg, 775 mg/kg, 800 mg/kg,825 mg/kg, 850 mg/kg, 875 mg/kg, 900 mg/kg, 925 mg/kg, 950 mg/kg, 975mg/kg or 1000 mg/kg, or may range between any two of the foregoingvalues.

In some embodiments, the small thiol composition is administered at atotal daily dose of from approximately 0.25 g/m² to 4.0 g/m² bodysurface area, e.g., at least about 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9,1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2 g/m², or up toabout 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0,2.2, 2.5, 2.7, 3.0, 3.25, 3.5 or 3.75 g/m² or may range between any twoof the foregoing values. In some embodiments, the small thiolcomposition may be administered at a total daily dose of about 0.5-2.0g/m² body surface area, or 1-1.5 g/m² body surface area, or 1-1.95 g/m²body surface area, or 0.5-1 g/m² body surface area, or about 0.7-0.8g/m² body surface area, or about 1.35 g/m² body surface area, or about1.3 to about 1.95 grams/m2/day, or about 0.5 to about 1.5 grams/m2/day,or about 0.5 to about 1.0 grams/m2/day, preferably at a frequency offewer than four times per day, e.g. three, two or one times per day.Salts or esters of the same active ingredient may vary in molecularweight depending on the type and weight of the salt or ester moiety. Foradministration of an enteric dosage form, e.g., a tablet or capsule orother oral dosage form comprising the enterically-coated smalldiffusible thiol composition, a total weight in the range ofapproximately 100 mg to 1000 mg is used. In various embodiments, thetablet or capsule comprises 25, 50, 75, 100, 125, 150, 175, 200, 225,250, 275, 300, 400 or 500 mg active ingredient, and multiple tablets orcapsules are administered to reach the desired dosage.

Combination Therapy

Therapeutic compositions described herein can also be administered incombination with adjunct therapy used in treatment of excitotoxicity andneurodegenerative diseases, such as antipsychotics, antidepressants,vesicular monoamine transporter (VMAT)-inhibitors such as tetrabenazine,dopamine inhibitors, laquinimod, CNS-immunomodulators, neuroprotectivefactors, BDNF and agents that upregulate BDNF, ampakines, positivemodulators of AMPA-type glutamate receptors, activators of BDNF receptorTrkB and gene therapy.

Antidepressants include: SSRI antidepressants, such as fluoxetine,citalopram and paroxetine, tricyclic antidepressants, such asamitriptyline, other types of antidepressants, including mirtazapine,duloxetine and venlafaxine.

Antipsychotic medication includes risperidone, olanzapine, aripiprazole,tiapride and quetiapine, benzodiazepines, such as clonazepam anddiazepam, and mood stabilizers, such as carbamazepine.

In some embodiments, the methods (or uses) described herein furthercomprise administering a further therapeutic agent selected from thegroup consisting of tetrabenazine, laquinimod, BDNF, ampakines,fluoxetine, citalopram, paroxetine, amitriptyline, mirtazapine,duloxetine, venlafaxine, risperidone, olanzapine, aripiprazole,tiapride, quetiapine, clonazepam diazepam and carbamazepine.

The small thiol composition and other drugs/therapies can beadministered in combination either simultaneously in a singlecomposition or in separate compositions. Alternatively, theadministration is sequential. Simultaneous administration is achieved byadministering a single composition or pharmacological proteinformulation that includes both the small diffusible thiol compositionand other therapeutic agent(s). Alternatively, the other therapeuticagent(s) are taken separately at about the same time as apharmacological formulation (e.g., tablet, injection or drink) of thesmall thiol composition.

In various alternatives, administration of the small thiol compositioncan precede or follow administration of the other therapeutic agent(s)by intervals ranging from minutes to hours. For example, in variousembodiments, it is further contemplated that the agents are administeredin a separate formulation and administered concurrently, withconcurrently referring to agents given within 30 minutes of each other.

In embodiments where the other therapeutic agent(s) and the small thiolcomposition are administered separately, one would generally ensure thatthe small thiol composition and the other therapeutic agent(s) areadministered within an appropriate time of one another so that both thesmall thiol composition and the other therapeutic agent(s) can exert,synergistically or additively, a beneficial effect on the patient. Forexample, in various embodiments the small thiol composition isadministered within about 0.5-6 hours (before or after) of the othertherapeutic agent(s). In various embodiments, the small thiolcomposition is administered within about 1 hour (before or after) of theother therapeutic agent(s).

In another aspect, in a method to treat excitotoxicity disorders furthercomprising administering an agent that inhibits the transported, theagent that inhibits is administered prior to administration of the smallthiol composition. Prior administration refers to administration of theagent that inhibits x_(c) ⁻ within the range of one week prior totreatment with small thiol composition, up to 30 minutes beforeadministration of small thiol composition. It is further contemplatedthat the agent that inhibits is administered subsequent toadministration of the small thiol composition. Subsequent administrationis meant to describe administration from 30 minutes after small thiolcomposition treatment up to one week after small thiol administration.

In various embodiments, the effects of small thiol compositions incombination with an agent that inhibits x_(c) ⁻ on the symptoms of theexcitotoxicity disease or disorder as described herein are measured asimprovements in disease symptoms described above, or are measured as aslowing or decrease in the time of progression of a disease symptom,e.g., a slowed progression of total motor score can be considered animprovement in a disease symptom.

Kits

The disclosure also provides kits for carrying out the methods of thedisclosure. In various embodiments, the kit contains, e.g., bottles,vials, ampoules, tubes, cartridges and/or syringes that comprise aliquid (e.g., sterile injectable) formulation or a solid (e.g.,lyophilized) formulation. The kits can also contain pharmaceuticallyacceptable vehicles or carriers (e.g., solvents, solutions and/orbuffers) for reconstituting a solid (e.g., lyophilized) formulation intoa solution or suspension for administration (e.g., by injection),including without limitation reconstituting a lyophilized formulation ina syringe for injection or for diluting concentrate to a lowerconcentration. Furthermore, extemporaneous injection solutions andsuspensions can be prepared from, e.g., sterile powder, granules, ortablets comprising a small thiol-containing composition and/or acomposition comprising an inhibitor of x_(c) ⁻ transporter. The kits canalso include dispensing devices, such as aerosol or injection dispensingdevices, pen injectors, autoinjectors, needleless injectors, syringes,and/or needles. In various embodiments, the kit also provides an oraldosage form, e.g., a tablet or capsule or other oral formulationdescribed herein, of the small thiol composition for use in the method.The kit also provides instructions for use.

While the disclosure has been described in conjunction with specificembodiments thereof, the foregoing description as well as the exampleswhich follow are intended to illustrate and not limit the scope of thedisclosure. Other aspects, advantages and modifications within the scopeof the disclosure will be apparent to those skilled in the art.

EXAMPLES

It was recently discovered that culture of neuronal cells in typicalcell culture media such as DMEM and Neurobasal media, along with mostother tissue culture media used for ex-vivo maintenance of neuronalcells, are inately excitotoxic (Maggioni, et al., Neuroreport 26,320-324, 2015; Bardy et al., Proc Natl Acad Sci USA 112, E2725-2734,2015). Survival in such media depends on a cocktail of antioxidantadditives, identified empirically, which support the antioxidantdefenses of the neurons themselves, but deprive cell-based models ofphysiological relevancy. Measuring the effect of sulfur amino acidstarvation under these conditions is still possible, with the additionof an inhibitor of the cystine/glutamate antiporter (x_(c)), the primarysource of cysteine to cells. Previous models were not able to testneuroprotective effects such as 1) glutamate receptor inhibition, 2)GABA receptor activation or inhibition, 3) voltage-gated calcium channelinhibition and 4) protein aggregation inhibition. It is contemplatedthat additional assays reveal that the captons herein inhibit proteinaggregation and inhibit receptor-based mechanisms, including GABApotentiation, glutamate receptor inhibition or voltage-gated calciumchannel blockade, by the products of reaction between the present thiolsand ROS.

In order to identify molecules that could act therapeutically toeffectively treat neurological disease, thiol compounds were screenedfor the ability to relieve sulfur amino acid starvation using mouse Q111striatal neurons grown in DMEM with 5-10 mM glutamate. High glutamateprevents cystine import with no significant additional impact resultingfrom glutamate receptor activation (NMDA, AMPA), which occurs in DMEM onits own. Almost all captons rescue cells under such conditions bycleaving cystine in the extracellular space, permitting import ofcysteine directly through alternative transporters (ASCT, aka SLC1A4 andSLC1A5), relieving sulfur amino acid starvation. PCT/US2016/040637describes the striatal neuron assay and the initial selection criteriafor captons. In addition to the above criteria, small thiols havingsimilarities to GABA or taurine are then selected for us in thefollowing assays to determine their neuroprotective effects.

Example 1—Measuring Oxidative Stress and its Prevention by Captons

While the assay with Q111 striatal neurons may measure the ability torescue sulfur starvation, the previous assay does not measure rescuefrom excitotoxicity and the effects on neurotransmission andneuroprotection mediated by the small thiol compounds. The ability oftest compounds to inhibit glutamate-induced excitotoxicity(neuroprotection) in St-HdhQ111/111 cells is determined by incubatingthe small thiol compounds with cells for 60 min at 33° C., 95% (v:v)air/5% (v:v) CO₂ in BrainPhys complete media (STEMCELL Technologies,Vancouver, British Columbia, Canada). Following this, excitotoxicity isinduced by the addition of 0.5 mM L-glutamate for 24 hours. Cellviability is assessed by measuring ATP levels, e.g., using aluminescent-based CellTitre Glo assay (Promega). Compoundneuroprotection (% cell survival) is expressed as a % of the effectrecorded with 100 μM cysteamine (denoted as 100% cell survival).

It is expected that the tested compounds result in high levels of cellsurvival (e.g., at least 50% cell survival when expressed as a % of theeffect for 100 μM cysteamine), including levels of cell survival highlysimilar to that provided by cysteamine in this particular system (e.g.,at least 80% cell survival when expressed as a % of the effect for 100μM cysteamine), suggesting that these compounds have similarneuroprotective effects compared to cysteamine.

Example 2—Protein Aggregation and its Prevention by Captons

The ability of test compounds to diminish aggregate formation in cellstreated with hydrogen peroxide is determined. Briefly, MyCell SOD1(G93A) neurons (CDI, Madison, Wis.) are cultured in 95% (v:v) air/5%(v:v) CO₂ in BrainPhys complete media (STEMCELL Technologies).Excitotoxic stress is induced by the addition of 0.5 mM L-glutamate for2 hours, with and without capton or controls. Cells are harvested,pelleted and snap frozen. Frozen whole-cell pellets are homogenized inlysis buffer (25 mM Tris, pH 7.8, supplemented with protease inhibitors)at 4° C. by brief sonication and cleared by centrifugation at 18,000×g.Soluble SOD1-containing cleared supernatants are snap frozen for lateranalysis. Insoluble SOD1 (aggregated) is extracted from the lysed cellpellet. Pellets are re-suspended in 1 mL washing buffer (50 mM Tris HClpH 7.4, 100 mM NaCl, 10% glycerol (v:v), 1% Triton X-100 (v:v), 0.5%NP-40 (v:v) with protease inhibitors by vortexing and centrifuged (10min) at 18,000×g at 4° C. 4 times. The washed pellet is re-suspended insolubilization buffer (50 mM Tris HCl pH 7.4, 100 mM NaCl, 10% glycerol,1% Triton X-100, 250 μM DTT, 1 mM EDTA, 2.5% SDS, with proteaseinhibitors, by vortexing, heated to 100° C. for 20 min, sonicated for 30min, and heated again before centrifuging at 18,000×g for 10 min at 25°C. Total protein concentrations in the soluble and insoluble fractionsare determined by Bradford assay. Samples are subjected to SDS-PAGEunder reducing conditions and blotted to PVDF. Western blot analysisused to measure relative levels of soluble and insoluble SOD1 are probedwith an anti-SOD1 antibody (Calbiochem, 574597) and an anti-tubulinantibody to normalize between lanes.

It is expected that treatment of cells with captons will significantlydiminish the amount of insoluble SOD1 compared to soluble SOD1. Similarassays can be performed for TDP-43 aggregation or tau aggregation inappropriate cell-culture models.

Example 3—Reduction of Glutamate-Induced Excitotoxic Stress andModulation of GABA Pathways by Oxidized Captons (O-Captons)

MyCell SOD1 (G93A) neurons (CDI, Madison, Wis.) are plated at a densityof 20,000 cells/well in 384-well format in BrainPhys medium (STEMCELLTechnologies, Vancouver, British Columbia, Canada) with antioxidants, 1μg/mL laminin and neuronal growth factor supplements. Pre-coatedpoly-D-lysine (PDL) plates are coated with matrigel as a matrixaccording to standard protocol. Half the medium is changed every 3 daysfor 3 weeks. Cells are treated with either glutamate receptorantagonists, GABA receptor agonists, GABA receptor antagonists, or VGCCblockers in the presence or absence of either captons or o-captons for30 min. Cells are then dosed with glutamate at 500 μM. At varioustimepoints, cells are assayed for viability using CellTiter-Glo 2.0 orcalcium content using a total intracellular calcium kit or ROS usingappropriate, commercially-available test kits. Cells are on otheroccasions assayed for mitochondrial stress or mitophagy also usingappropriate test kits. To measure the ability and mechanism ofcapton-rescue from glutamate excitotoxicity, cells are pre-treated witha fixed concentration of glutamate (e.g., 5-10 mM) for an hour and thendifferent concentrations of captons or o-captons are applied to thecells for an additional 24 hours. Harvested cells are then tested asdescribed above.

It is contemplated that captons and o-captons improve cell-viability,reduce intracellular calcium concentrations, relieve mitochondrialstress and enhance mitophagy in cells under glutamate stress. GABAergicagents, transaminase inhibitors and reuptake inhibitors are hypothesizedto be of no additional benefit over o-captons with similar activities.It is hypothesized that calcium channel blockers will be of noadditional advantage over gabapentinoid-like o-captons.

Example 4—Measurement of Mitigation of Seizure Activity and OxidativeStress by Captons in a Kainic Acid-Induced Model of Temporal LobeEpilepsy

Male, Sprague-Dawley rats, (aged 9-11 weeks) are used in the study.Controls, test articles and kainic acid (KA, 15 mg/kg body weight; 10mg/ml in normal saline) are administered subcutaneously (sc) to allgroups. KA (15 mg/kg body weight) triggers hyperexcitation andexcitotoxic damage within 2 hours. Group 1, pretreated with saline, noKA; Group 2, pretreated with saline followed an hour later with KA;Group 3, pretreated with capton test article followed an hour later withKA; Group 4, pretreated with topiramate (positive control) then KA anhour later; Group 5, no pretreatment, saline and KA co-administered;Group 6, no pretreatment, capton and KA co-administered. Following KAadministration, animals are monitored for 4 hours and the time-to-onsetof seizures noted. Diazepam (10 mg/kg body weight) is administeredintraperitoneally 90 min after the first seizure. Behavioral change isobserved using an open field test (OFT) to assess locomotor activity in15 minutes in an unobstructed space. Activity is recorded using avideo-tracking system. Subjects are euthanized by deep anesthesia withketamine/xylazine, followed by brief perfusion with cold saline anddecapitation. Cortices are removed, weighed and washed with cold saline.One half of each cortex is homogenized in ice-cold PBS and clarified bycentrifugation. Homogenate is assayed for lipid peroxidation andanti-oxidant status. The intact cortical hemisphere is immediatelyfixed, embedded, sectioned and stained for automated neuron counting andimmunohistochemical assessment of damage.

Example 5—In Vitro Oxidation Assay

In order, 4 μL of water or an appropriate aqueous metal solution (1 μMCu(I)Cl or 5 μM Fe(II)SO₄) was combined with 92 μL hydrogen peroxide(200 μM, freshly diluted from 30%) in bicarbonate buffer (1.25%, pH7.8-8.2) and 4 μL of the capton (thiol) being assayed (0-100 μM) orthiol standard. The reactions were allowed to proceed from 1 minute to24 hours, and were then quenched with 4 μL of 10 mM TCEP and shaken for5 minutes to destroy peroxide and reduce disulfides. A 10 μL aliquot ofthe TCEP-quenched reaction was removed, and it was added to 90 μL ABD-Fsolution (1 mM in 20 mM HEPES pH 7). Fluorescence was measured at 513 nmafter excitation at 389 nm after 30 minutes.

Results are presented in FIGS. 3, 4, and 5.

Example 6—Pharmacokinetics and ADME of Captons in Normal and KainicAcid-Treated CD Rats

The objective of the study was to investigate the pharmacokinetics andADME of two capton molecules, capton-003 and capton-004, after a singleintravenous injection into healthy CD rats, as well as CD rats treatedwith the CNS excitotoxin, kainic acid. In particular, half-life,clearance, and area under the pharmacokinetic curve were determined onthe basis of capton tissue levels and those of an oxidized metabolite(ocapton).

Experiments were performed as specified on the license authorized by theNational Animal Experiment Board of Finland (Elainkoelautakunta, ELLA)and according to the National Institutes of Health (Bethesda, Md., USA)guidelines for the care and use of laboratory animals. In total, 111 CDrats (250-275 grams) were used for the study. Animals were housed at astandard temperature (22±1° C.), in a light-controlled environment (darkfrom 8 pm-7 am) with ad libitum access to food and water.

Animals were grouped as follows, with a summary presented in Table B,below:

Group 1: control, 6 rats injected intravenously (i.v.) under lightisoflurane anesthesia with vehicle for capton derivatives (2 mL/kg) andsampled 1 hour after vehicle injection (N=6).

Group 2: 21 rats, 10 mg/kg capton-003, sampled 15 min (N=3); 30 min(N=3); 1 hour (N=3); 2 hours (N=3); 4 hours (N=3); 8 hours (N=3) and 24hours (N=3) after injection.

Group 3: 21 rats, capton-004.

TABLE B Group Group Dose Dosing Vol. ID Treatment size (N) Route (mg/kg)(mL/kg) 1 vehicle 6 i.v. 10 2 2 capton-003 21 i.v. 10 2 3 capton-004 21i.v. 10 2

Powdered capton materials were weighed and dissolved in enoughphosphate-buffered saline to afford the desired concentrations forinjection. Rats were assigned to treatment groups and tail-markedaccordingly with a Sharpie. Body weight, treatment group and treatmenttimes were recorded. A single intravenous injection of the vehicle ortest article (capton-003 or capton-004) were given to the rats at a doseof 10 mg/kg, with a dosing volume of 2 mL/kg.

Rats were deeply anesthetized with pentobarbital and blood samplescollected by cardiac puncture. Blood (500 μL) was initially collectedinto K2-EDTA microtubes. Samples were centrifuged (2500×g for 10 min at4° C.). Plasma supernatant fractions were isolated (−200 μL), frozen ondry ice, and stored at −80° C. until shipment on dry ice for subsequentdetection of capton and ocapton. Prior to analysis for captons, plasmasamples were thawed on ice, followed by immediate TCEP(tris(2-carboxyethyl)phosphine) addition (ice-cold) to a finalconcentration of 5 mM. Treated samples were then deproteinized usingacetonitrile with formic acid (also ice-cold) and supernatants kept coldand at low pH prior to LC-MS analysis. After blood collection, CSF wascollected from the cisterna magna. CSF clarity was recorded andcharacterized as clear, slightly-tinged, tinged, pink, or bloody. Ifscoring indicated tinged, pink or bloody, samples were clarified bycentrifugation. Sample tubes were tared and CSF added. The CSF sampleweight was then determined and recorded. CSF samples were frozen on dryice and stored at −80° C. until shipment on dry ice for subsequentdetection of capton and ocapton. Prior to analysis, CSF samples werethawed on ice and treated as previously described for plasma. After CSFcollection, the rats were perfused by cardiac puncture with saline anddecapitated. The top of the skull was removed, along with pial vessels,and the entire brain of each animal extracted. Brain tissue was frozenon dry ice and stored at −80° C. Prior to capton analysis, brain tissueswere thawed on ice, followed by immediate addition of extraction buffer(20 mM ammonium formate, 5 mM TCEP, pH 3.5; pH adjusted with formicacid) and tissue extraction achieved by sonication. Disulfide bonds intissue homogenates were reduced by incubation at 37° C. for 30 min.After the reduction step, PCA (perchloric acid) was added to thehomogenate to a final concentration of 100 mM and tissue homogenatescentrifuged (30 min, 4° C., 13,000 rpm). Supernatants were stored astissue extracts at −80° C. until analysis.

Sample analysis was performed using liquid chromatography (LC) andtandem mass spectrometry (MS) analysis. Prior to the analysis of studycompounds in plasma, CSF, and brain tissue samples, method developmentwas performed to ensure that robust and reliable quantification waspossible. All compounds were first tuned individually by direct infusion(MS-only) in ESi+ mode on an API-4000 or API-5000 triple-quadrupolemass-spectrometer equipped with a Turbo Ion Spray interface (Sciex).Sample resolution by HPLC (HILIC amide or C18 reversed-phase) wasperformed prior to MS analysis. For HILIC, an eluent of 70% acetonitrilein 2 mM ammonium formate, 3.6 mM formic acid was employed; for C18, agradient of acetonitrile in ultra-purified water, 0.1% formic acid wastested. Chromatographic properties, such as retention time (stability),peak shape, response, separation from isomers, and stability (initiallyin solvent, later in matrix), were evaluated using known standards.Compound standards were spiked into the biological matrices of interestand bioanalytical parameters captured (e.g., matrix interference, matrixbackground). Lowest-limit-of-quantitation (LLOQ) for each analyte wasdetermined after achieving 1) adequate signal-to-noise ratios, 2)adequate discrimination from background peaks exceeding noise (ifpresent), 3) calculated accuracy. Quality during the analysis of theunknown study samples was ensured through the use of known standards atthree concentration levels, with blanks. For stability determinationduring analysis, processed samples from the different matrices were keptin the instrument's autosampler under acidic conditions at 4° C. Acidicconditions during LC-MS analysis (with 0.1% formic acid or formic acidin combination with ammonium formate) were maintained for stability.

Example 7—Effects of Kainic Acid on Capton Pharmacokinetics and ADME inCD Rats

The objective of the study was to investigate the pharmacokinetics ofcapton-003 and capton-004 after intravenous injection into CD ratspre-treated with kainic acid, an excitotoxin known to increase levels ofbrain reactive-oxygen species (ROS). In particular, half-life,clearance, and area under the pharmacokinetic curve were determined onthe basis of the levels of capton and an oxidized metabolite, ocapton(capton sulfonate), in the brain, CSF and blood plasma 1.25-25 h afteradministration of the test articles, except that rats were additionallyinjected with kainic acid (15 mg/kg, intraperitoneal) an hour after eachcapton.

All animal experiments were performed as specified in the licenseauthorized by the national Animal Experiment Board of Finland(Elainkoelautakunta, ELLA) and according to the National Institutes ofHealth (Bethesda, Md., USA) guidelines for the care and use oflaboratory animals. In total, 210 CD rats (250-275 g) were used for thestudy. Animals were housed at a standard temperature (22±1° C.) and in alight-controlled environment (on from 7 am to 8 pm) with ad libitumaccess to food and water.

Animals were grouped as follows, with a summary presented in Table C,below:

Group 1 (control): 35 rats were injected intravenously (i.v.) underlight isoflurane anesthesia with capton vehicle (2 mL/kg) and then, anhour later, with 15 mg/kg kainic acid intraperitoneally (i.p.). Ratswere sampled 15 min after kainate injection (N=5); 30 min (N=5); 1 h(N=5); 2 h (N=5); 4 h (N=5); 8 h (N=5) and 24 h (N=5).

Group 2 (capton-003): 35 rats were injected i.v. under light isofluraneanesthesia with 10 mg/kg capton-003 and then, an hour later, with 15mg/kg kainic acid intraperitoneally (i.p.). Rats were sampled 15 minafter kainate injection (N=5); 30 min (N=5); 1 h (N=5); 2 h (N=5); 4 h(N=5); 8 h (N=5) and 24 h (N=5).

Group 3 (capton-004): 35 rats were injected i.v. under light isofluraneanesthesia with 10 mg/kg capton-004 and then, an hour later, with 15mg/kg kainic acid intraperitoneally (i.p.). Rats were sampled 15 minafter kainate injection (N=5); 30 min (N=5); 1 h (N=5); 2 h (N=5); 4 h(N=5); 8 h (N=5) and 24 h (N=5).

TABLE C Group Group Route of Dose Dosing Vol. ID Treatment size (n)Admin. (mg/kg) (mL/kg) 1 capton vehicle 35 i.v. 10 2 1 kainate 35 i.p.15 2 2 capton-003 35 i.v. 10 2 2 kainate 35 i.p. 15 2 3 capton-004 35i.v. 10 2 3 kainate 35 i.p. 15 2

Rats were given a single i.v. injection of one of the two tested captonderivatives at a concentration of 10 mg/kg (Groups 2 and 3) or captonvehicle (Group 1). An hour later, all rats received a singleintraperitoneal injection of 15 mg/kg kainic acid. Rats were thensacrificed at 15 min, 30 min, 1 h, 2 h, 4 h, 8 h or 24 h post-kainicacid. Samples of the cerebrospinal fluid (CSF), blood plasma and brainwere then obtained for subsequent bioanalytical detection of capton andocapton.

The rats were assigned to the treatment groups and tail-markedaccordingly with a permanent marker. Records were made about bodyweight, treatment groups and treatment times.

A single intravenous administration of the vehicle or each of thestudied capton derivatives (capton-002, -003, -004, and -007) at a doseof 10 mg/kg was given to the rats. Kainate was dissolved in saline andadministered at a dose of 15 mg/kg i.p. in 1 h after capton/vehicleinjection. Dosing volumes in both cases was 2 mL/kg.

Results from the studies of Examples 6 and 7 are presented in FIGS. 6,7, 8, 9, and 10.

Example 8—Effects of Captons on Seizure Scoring in CD Rats

During the last 2 min prior to the dissection in Examples 6 and 7, ratswere observed for the presence of convulsant activity and itsmanifestations were scored according to the following scale: 0, normal;1, immmobilization, occasional “wet-dog shakes”; 2, head nodding,unilateral forelimb clonus, frequent “wet dog shakes”; 3, rearing,salivation, bilateral forelimb clonus; 4, generalized limbic seizureswith falling, running and salivation; 5, continuous generalized seizureswith tonic limbic extension, death.

Numerous modifications and variations in the invention as set forth inthe above illustrative examples are expected to occur to those skilledin the art. Consequently, only such limitations as appear in theappended claims should be placed on the invention.

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1. A method of treating a neurological disease or disorder, anexcitotoxicity disorder, a neurological disease or disordercharacterized by aggregation of TDP-43, or a neurological disease ordisorder characterized by aggregation of superoxide dismutase 1 (SOD1)protein comprising administering a small thiol compound having amolecular weight <500 daltons, a log P >0.8, and a TPSA <90 that can beoxidized by reactive-oxygen species after crossing the blood-brainbarrier to a sulfinic or sulfonic acid and wherein the oxidized compoundpossesses GABAergic, calcium channel inhibiting, glutamatergic or otherneurologic activity. 2.-4. (canceled)
 5. The method of claim 1, furthercharacterized by aggregation of tau protein.
 6. The method of claim 1,wherein the disease or disorder is amyotrophic lateral sclerosis (ALS),frontotemporal lobar degeneration, traumatic brain injury, chronictraumatic encephalopathy (CTE), Alzheimer's disease, ischemia orepilepsy.
 7. The method of claim 6 wherein the disease is familial orsporadic ALS.
 8. A method of preventing or ameliorating brain injurycaused by trauma comprising administering to a subject in need thereof asmall thiol compound having a molecular weight <500 daltons, a logP >0.8, and a TPSA <90 that can be oxidized by reactive-oxygen speciesafter crossing the blood-brain barrier to a sulfinic or sulfonic acidand where the oxidized compound possesses GABAergic, calcium channelinhibiting, glutamatergic or other neurologic activity.
 9. (canceled)10. The method of claim 1, wherein the compound reduces proteinaggregation, neuronal overexcitation or oxidative stress characteristicof neurodegenerative disorders.
 11. A method for treating orameliorating glutamate toxicity or slowing the degeneration of neuronsin a subject comprising administering an effective amount of a smallthiol compound having a molecular weight <500 daltons, a log P >0.8, anda TPSA <90 that can be oxidized by reactive-oxygen species aftercrossing the blood-brain barrier to a sulfinic or sulfonic acid andwhere the oxidized compound possesses GABAergic, calcium channelinhibiting, glutamatergic or other neurologic activity.
 12. The methodof claim 1, wherein the administration reduces neuronal glutamatetoxicity.
 13. (canceled)
 14. A method for slowing the degeneration ofneurons or treating or ameliorating glutamate toxicity in a subjectcomprising administering an effective amount of a compound of Formula I,II or III that can be oxidized by reactive-oxygen species after crossingthe blood-brain barrier to a sulfinic or sulfonic acid, and wherein theoxidized compound possesses GABAergic, calcium channel inhibiting,glutamatergic or other neurologic activity, wherein the compound ofFormula I, II, or III has the structure:

HS-L-NR⁹R¹⁰ (II), or

wherein: R¹ and R² are independently selected from the group consistingof H and C₁₋₅alkyl; or R¹ and R², taken together with the carbon atom towhich they are attached, form a 3-, 4-, 5-, 6-, 7-, or 8-memberedcarbocyclic ring; R³ and R⁴ are independently selected from the groupconsisting of H and C₁₋₅alkyl; or R³ and R⁴, taken together with thecarbon atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or8-membered carbocyclic ring; G is selected from the group consisting of—NR⁵R⁶ and —CR⁷R⁸NR⁵R⁶; R⁵ and R⁶ are independently selected from thegroup consisting of H and C₁₋₅alkyl; or R⁵ and R⁶, taken together withthe nitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-,or 8-membered heterocyclic ring; R⁷ and R⁸ are independently selectedfrom the group consisting of H and C₁₋₅alkyl; or R⁷ and R⁸, takentogether with the carbon atom to which they are attached, form a 3-, 4-,5-, 6-, 7-, or 8-membered carbocyclic ring; R² and R⁶, taken togetherwith the atoms to which they are attached, optionally form a 4-, 5-, 6-,7-, 8-, 9-, or 10-membered heterocyclic ring; R⁴ and R⁶, taken togetherwith the atoms to which they are attached, optionally form a 4-, 5-, 6-,7-, 8-, 9-, or 10-membered heterocyclic ring; R⁴ and R⁸, taken togetherwith the atoms to which they are attached, optionally form a 3-, 4-, 5-,6-, 7-, or 8-membered carbocyclic ring; R² and R⁸, taken together withthe atoms to which they are attached, optionally form a 3-, 4-, 5-, 6-,7-, or 8-membered carbocyclic ring; R² and R⁴, taken together with theatoms to which they are attached, optionally form a 3-, 4-, 5-, 6-, 7-,or 8-membered carbocyclic ring; L is a hydrocarbon linking group; R⁹ andR¹⁰ are independently selected from the group consisting of H,C₁₋₅alkyl, and CO(C₁₋₅alkyl); or R⁹ and R¹⁰, taken together with thenitrogen atom to which they are attached, form a 3-, 4-, 5-, 6-, 7-, or8-membered heterocyclic ring; A is a 3 to 8 membered heterocyclic ringcontaining one N atom; n is 0, 1, 2, or 3; wherein a C₁₋₅ alkyl moiety,wherever it occurs, can optionally comprise a double bond; and wherein aC₁₋₅ alkyl, 3-, 4-, 5-, 6-, 7-, or 8-membered carbocyclic orheterocyclic moiety, wherever it occurs, can optionally be substitutedwith from one to three substituents which are not further substitutedand which are independently selected from the group consisting of —CN,thio, halo, hydroxy, C₆₋₁₀ aryl, C₁₋₆ alkyl, C₂₋₆ alkenyl,C₃₋₆cycloalkyl, 5- or 6-membered heterocycloalkyl containing 1-3heteroatoms selected from O, N, and S, CO₂H, CO₂C₁₋₆alkyl,C(O)C₁₋₆alkyl, CO₂NH₂, CO₂NHC₁₋₆alkyl, and —CO₂N(C₁₋₆alkyl)₂. 15.(canceled)
 16. The method of claim 14, wherein the compound has thestructure of Formula Ia, Ib, Ic, Id, or Ie:


17. The method of claim 14, wherein the compound has the structure ofFormula IIIa:

wherein R¹¹ is selected from the group consisting of H and C₁₋₅alkyl.18.-28. (canceled)
 29. The method of claim 1, wherein the administrationimproves one or more symptoms of diminished motor function, mobility,cognitive ability, or other symptoms of an excitotoxicity disorder. 30.The method of claim 29, wherein one or more symptoms include diminishedmotor function, mobility, cognitive ability, or other symptoms of anexcitotoxicity disorder.
 31. The method of claim 1, wherein the compoundexhibits neuroprotective effects in a neuronal tissue-culture model ofexcitotoxicity, oxidative stress, glutamate overstimulation, elevatedintracellular calcium, GABA receptor function, mitochondrial stress orthe consequences of these phenomena.
 32. The method of claim 1, whereinthe compound or its oxidized equivalent improves cell-viability, reducescalcium transport, relieves mitochondrial stress, enhances mitophagy,modulates GABA activity, glutamate activity or voltage-gated calciumchannel activity in a subject.
 33. The method of claim 1, wherein thecompound; i) reduces levels of ROS in the CNS; ii) increasesintracellular cysteine and the sum of all intracellular low-molecularweight thiols; iii) reduces weak metal-protein interactions throughbinding of unchaperoned metal-ions; and/or iv) reduces intracellularprotein aggregation that is dependent on oxidation of cysteine.
 34. Themethod of claim 1, wherein the compound is a compound of Table A. 35.The method of claim 14, wherein the compound is a compound of Table A.36. The method of claim 34, wherein the compound is selected from thegroup consisting of 3, 4, 5, 9, 10, 15, 16, 18, 19, 20, 21, 22, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, 47, 48,49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67,68, 69, 70, 71, 72, 73, 77, 78, 79, 80, 81, 83, 85, 86, 87, 88, 90, 92,95, 96, 97, 101, 103, 105, 106, 107, 108, 109, 110, 112, 113, 116, 117,118, 119, 120, 121, 123, 126, 127, 128, 129, 130, 131, 132, 134, 135,137, 138, 139, 140, 142, 143, 145, 151, 158, 170, and
 175. 37. Themethod of claim 35, wherein the compound is selected from the groupconsisting of 3, 4, 5, 9, 10, 15, 16, 18, 19, 20, 21, 22, 27, 28, 29,30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 44, 45, 47, 48, 49,50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 66, 67, 68,69, 70, 71, 72, 73, 77, 78, 79, 80, 81, 83, 85, 86, 87, 88, 90, 92, 95,96, 97, 101, 103, 105, 106, 107, 108, 109, 110, 112, 113, 116, 117, 118,119, 120, 121, 123, 126, 127, 128, 129, 130, 131, 132, 134, 135, 137,138, 139, 140, 142, 143, 145, 151, 158, 170, and 175.